Monoamine oxidase (MAO) inhibitors can regulate the level of monoamines and their neurotransmitter release in different brain regions and in the body (including dopamine, norepinephrine, and serotonin). MAO inhibitors (MAOI) can thereby affect the modulation of neuroendocrine function, respiration, mood, motor control and function, focus and attention, concentration, memory and cognition, and the mechanisms of substance abuse. MAOI have been demonstrated to have effects on attention, cognition, appetite, substance abuse, memory, cardiovascular function, extrapyramidal function, pain and gastrointestinal motility and function. The distribution of MAO in the brain is widespread and includes the basal ganglia, cerebral cortex, limbic system, and mid and hind-brain nuclei. In the peripheral tissue, the distribution includes muscle, the gastrointestinal tract, the cardiovascular system, autonomic ganglia, the liver, and the endocrinic system. Regulation of monoamine levels in the body has been shown to be effective in numerous disease states including depression, anxiety, stress disorders, and withdrawal symptoms, among others.
It has been suggested that cigarette smoke may have irreversible inhibitory effect towards monoamine oxidase (MAO). A. A. Boulton et al., “Biogenic Amine Adducts, Monoamine Oxidase Inhibitors, and Smoking,” Lancet, 1 (8577):114-155 (1988), reported that the MAO-inhibiting properties of cigarette smoke may help to explain the protective action of smoking against Parkinson's disease and also observed that patients with mental disorders who smoke heavily do not experience unusual rates of smoking-induced disorders. It was suggested that smoking, as an MAOI, may protect against dopaminergic neurotoxicity that leads to Parkinson's disease and that the MAO-inhibiting properties of smoking may result in an anti-depressive effect in mental patients.
L. A. Carr et al., “Effects of Tobacco Smoke Constituents on MPTP Induced Toxicity and Monoamine Oxidase Activity in the Mouse Brain,” Life Sciences, 48:1173-1177 (1991), found that nicotine, 4-phenylpyridine and hydrazine prevented the decrease in dopamine metabolite levels induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice, but there was no significant effect on dopamine levels. Because tobacco smoke particulate matter caused a marked inhibition of MAO-A and MAO-B activity when added in vitro, it was suggested that one or more unidentified substances in tobacco smoke are capable of inhibiting brain MAO and perhaps altering the formation of the active metabolite of MPTP.
J. S. Fowler et al., “Inhibition of Monoamine Oxidase B in the Brain of Smokers,” Nature (Lond), 379(6567): 733-736 (1996), found that the brains of living smokers showed a 40% decrease in the level of MAO-B relative to non-smokers or former smokers. MAO inhibition was also reported as being associated with decreased production of hydrogen peroxide.
It has also been suggested that nicotine may not be the only constituent of tobacco responsible for tobacco addiction. J. Stephenson, “Clues Found to Tobacco Addiction,” Journal of the American Medical Association, 275(16): 1217-1218 (1996), discussing the work of Fowler, et al., pointed out that the brains of living smokers had less MAO-B compared with the brains of nonsmokers or former smokers. MAO-B is an enzyme involved in the breakdown of dopamine, which is a pleasure-enhancing neurotransmitter. The results suggested that the inhibition of MAO-B in the brains of smokers may make nicotine more addictive by slowing down the breakdown of dopamine, thereby boosting its levels. The findings provided an explanation as to why cigarette smokers were less susceptible to developing Parkinson's disease. Further, the findings suggested that MAOI could be used for smoking cessation. Williams et al. U.S. Pat. No. 6,350,479 reported that the minor tobacco alkaloids anabasine, anatabine, and nornicotine exhibited MAO inhibitory effects against MAO-A and MAO-B.
Inflammation is a protective response to harmful stimuli, such as oxidative stress, irritants, pathogens, and damaged cells. The inflammatory response involves the production and release of inflammatory modulators that heal injured tissue and destroy damaged cells, by directly or indirectly producing and/or signaling the release of agents that produce reactive oxygen species. Thus, an appropriate inflammatory response involves a balance between the destruction of damaged cells and the healing of injured tissue.
Some anti-inflammatory compounds function by reducing transcription mediated by nuclear factor κB (NFκB). NFκB is a transcription factor which operates in cells involved in inflammatory and immune reactions. NFκB-mediated transcription is associated with numerous disorders including, for example, immune or autoimmune disorders, arthritis, various cancers, upper respiratory tract infections, neurodegenerative diseases, and so forth. Williams U.S. 2012/0245202 reported that anatabine is effective for treating disorders having a NFκB-mediated inflammatory component.
The role of nitric oxide (NO) in tumorigenesis has been well-studied. A large majority of human tumors appear to progress owing to NO resulting from inducible nitric oxide synthase (iNOS), further stimulated by pro-inflammatory cytokines. Conversely, in some cases, NO is associated with induction of apoptosis and tumor regression. This dichotomy of NO is attributable to the complexity of signaling pathways in tumor cells, which may respond to NO very differently depending on concentration. Also, NO alters many signaling pathways through chemical modifications, such as the addition of S-nitrosothiols and nitrosotyrosine to target proteins altering various biological pathways. As a consequence, iNOS inhibitors have been designed and developed to inhibit various organ site cancers including the colon.
It would be desirable to develop alternative compounds for treating indications such as depression, substance addiction, smoking cessation, pain, and/or disorders associated with chronic inflammation.